Abstract: The opioid dependence (OD) epidemic in the US affects a high proportion of women of reproductive age. OD impairs interpersonal interactions including parenting. Mothers with OD exhibit caregiving deficits leading to child maltreatment, high utilization of foster care, and intergenerational perpetuation of OD. Importance of maternal OD as treatment target is further increased because, unlike cocaine where abstinence is the goal, the recommended treatment for maternal OD is agonist maintenance, which entails continued exposure to exogenous opioids after remission. Yet, while opioid abuse and dependence are at an all time high, knowledge on the phenomenology and neurobiological correlates of maternal behaviors in OD is profoundly underrepresented in the literature. Infantile cues elicit motivation for caregiving in healthy people, even if they?re unrelated to the child. Functional magnetic resonance imaging (fMRI) studies show that this behavior may be conveyed by the mesocorticolimbic (MCL) system, which includes the nucleus accumbens (NAcc) and mediates motivation and reward. ?Baby schema?, a set of juvenile features (e.g. large head and big eyes), is perceived as ?cute?, elicits motivation for caregiving, and parametrically activates the NAcc in healthy unrelated nulliparous women. These findings suggest that baby schema is what makes babies ?cute? and is the natural reinforcer that initiates caregiving behaviors through the MCL system. Preclinical data indicate that (1) endogenous opioids enable maintenance of social bonds including maternal attachment and (2) exogenous opioid agonists cause complex changes in maternal caregiving. Our preliminary data show reduced brain response to baby schema in heroin abusing women, suggesting that these preclinical observations may extend to humans. Our project will prospectively evaluate the brain response to baby schema as a probe of caretaking in mothers with babies who are enrolled in a methadone medication-assisted treatment (MAT) for opioid dependence. Building on the limited largely preclinical data from multiple disciplines and our preliminary fMRI studies in healthy and OD women, we hypothesize that the baseline brain fMRI response to baby schema in OD mothers will be lower than in controls and predict quality of parenting and child development at a six-month follow up visit. These data would enable further research on the markers of vulnerability to caregiving deficits in OD mothers and science-based preventive interventions aimed at improving parenting skills in OD mothers, which could be extended to other substances. This high-risk research has the potential to change the current thinking and practice on the effects of opioid agonists on maternal behaviors, and is a timely contribution to the efforts to stem the ongoing opioid abuse epidemic.